The present invention relates to a novel 6-O-methylerythromycin A crystal form, a process for preparing the crystal form, and a method for using the crystal form to prepare a 6-O-methylerythromycin A crystal form II.
6-O-methylerythromycin A (Clarithromycin) is a semisynthetic macrolide antibiotic of the formula: 
which exhibits excellent antibacterial activity against gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia. The compound has demonstrated useful properties as a therapeutic agent for infections of the upper respiratory tract in children and adults.
The crystalline form of a compound can exist as different crystal forms (or polymorphs), which differ in the way the molecules are arranged and packed in the crystal lattice. Previously, the 6-O-methylerythromycin A compound has been reported in the literature as existing in at least three distinct crystal forms. For the sake of identification, these crystal forms have been designated xe2x80x9cForm 0xe2x80x9d, xe2x80x9cForm Ixe2x80x9d, and xe2x80x9cForm II.xe2x80x9d The unique physical properties of each crystal form is reflected in their infrared spectrum, powder X-ray diffraction pattern, and/or differential scanning crystallography (DSC), by which each crystal form can be individually indentified.
Form I of 6-O-methylerythromycin A was prepared according to the methods as described in U.S. Pat. No. 5,858,986, issued on Jan. 12, 1999, and first identified as exhibiting the X-ray powder diffraction pattern having the 2-theta angles 5.16xc2x0xc2x10.2, 6.68xc2x0xc2x10.2, 10.20xc2x0xc2x10.2, 12.28xc2x0xc2x10.2, 14.20xc2x0xc2x10.2, 15.40xc2x0xc2x10.2, 15.72xc2x0xc2x10.2, and 16.36xc2x0xc2x10.2.
The process for preparing Form II, which is the marketed crystal form of 6-O-methylerythromycin A, was disclosed in U.S. Pat. No. 5,844,105, issued on Dec. 1, 1998. The Form II X-ray powder diffraction pattern was identified as the following, wherein the 2-theta angles are 8.52xc2x0xc2x10.2, 9.48xc2x0xc2x10.2, 10.84xc2x0xc2x10.2, 11.48xc2x0xc2x10.2, 11.88xc2x0xc2x10.2, 12.36xc2x0xc2x10.2, 13.72xc2x0xc2x10.2, 14.12xc2x0xc2x10.2, 15.16xc2x0xc2x10.2, 16.48xc2x0xc2x10.2, 16.92xc2x0xc2x10.2, 17.32xc2x0xc2x10.2, 18.08xc2x0xc2x10.2, 18.40xc2x0xc2x10.2, 19.04xc2x0xc2x10.2, 19.88xc2x0xc2x10.2, and 20.48xc2x0xc2x10.2.
Form 0 exists as a solvate of 6-O-methylerythromycin A. The identification and methods for preparing the isolated form Form 0 solvate are first described in the U.S. Pat. No. 5,945,405, which issued on Aug. 31, 1999. The representative X-ray powder diffraction pattern of the Form 0 solvate comprises the 2-theta angles 4.851xc2x0xc2x10.2, 6.498xc2x0xc2x10.2, 7.615xc2x0xc2x10.2, 9.169xc2x0xc2x10.2, 10.154xc2x0xc2x10.2, 11.009xc2x0xc2x10.2, 11.618xc2x0xc2x10.2, 12.495xc2x0xc2x10.2, 13.772xc2x0xc2x10.2, 14.820xc2x0xc2x10.2, 16.984xc2x0xc2x10.2, 18.221xc2x0xc2x10.2, 18.914xc2x0xc2x10.2, and 19.495xc2x0xc2x10.2.
The Form 0 solvate can be prepared by the recrystallization of 6-O-methylerythromycin A in a suitable solvent, such as ethanol, isopropyl acetate, isopropanol, and tetrahydrofuran. At temperatures of about room temperature up to about 50 xc2x0 C., the solvent molecules are released from the crystal lattice of Form 0 and the resulting crystal structure corresponds to Form I. Form I converts into Form II at controlled temperatures of from about 100-105xc2x0 C. Conversion of the Form 0 crystal solvate into a Form II crystal is accomplished via a Form I intermediate. The Form 0, Form I and Form II crystal structures have been each been identified as an orthorhombic crystal system.
It has been unexpectedly discovered that 6-O-methylerythromycin A can be prepared as a new crystalline polymorph. The new crystal structure of 6-O-methylerythromycin A is an acetonitrile solvate of 6-O-methylerythromycin A. The novel polymorph can be used as an intermediate to prepare a pharmaceutically acceptable 6-O-methylerythromycin A Form II crystal.
In one aspect, the invention relates to a novel crystal solvate of 6-O-methylerythromycin A, which is designated for the sake of identification as the Form III crystalline polymorph. The polymorph exists as a solvate, and can be represented by the structure 
wherein S is one, two or three acetonitrile solvent molecules. The polymorph can exist in a mixture with other forms of 6-O-methylerythromycin A or in a substantially pure form having at least 90% Form III polymorph.
Substantially pure Form III exhibits a characteristic X-ray powder diffraction pattern 9.05xc2x0xc2x10.2, 9.64xc2x0xc2x10.2, 11.80xc2x0xc2x10.2, 12.77xc2x0xc2x10.2, 15.28xc2x0xc2x10.2, 16.04xc2x0xc2x10.2, 16.55xc2x0xc2x10.2, 17.70xc2x0xc2x10.2, 18.17xc2x0xc2x10.2, 18.79xc2x0xc2x10.2, and 24.94xc2x0xc2x10.2. The crystal structure can be identified as a monoclinic crystal system. The crystallographic unit cell parameters of a single acetonitrile solvate crystal have been determined as having the following parameters: a is 10.591 (1) xc3x85; b is 18.036 (1) xc3x85; c is 11.555 (1) xc3x85; and xcex2 is 95.72 (1)xc2x0 to afford a cell volume of 2196.2 (3) xc3x853, wherein a, b and c are each a representative length of the crystal lattice and P is the diagonal.
In another aspect, the invention relates to a process for preparing a substantially pure Form III polymorph. The Form III polymorph can be prepared by treating 6-O-methylerythromycin A with acetonitrile to obtain a homogeneous solution; allowing the solution to equilibrate at ambient temperature; cooling the solution to a temperature of 0-5xc2x0 C. to form a solid precipitate in solution; and collecting the solid precipitate.
Yet another aspect of the invention relates to a process for preparing Form II of 6-O-methylerythromycin A from a substantially pure Form III polymorph. The process comprises drying a Form III polymorph at a temperature from about 80xc2x0 C. to about 180xc2x0 C. and isolating 6-O-methylerythromycin crystal Form II. Preferably, the process is accomplished at temperatures from about 90xc2x0 C. to about 105xc2x0 C.
Therefore, the invention provides novel crystal forms from which to obtain the 6-O-methylerythromycin product.